Abstract

In a recent work, we described the design and synthesis of arylnitroalkenes, able to scavenge macrophagederived oxidants, in particular peroxynitrite and peroxynitrite derived radicals. Four compounds emerged as potential leads, 1,1-dimethylamino-4-(2-nitro-1Z-ethenyl)benzene (1), 1,1-dimethylamino-4-(2-nitro-1Z-propenyl)benzene (2), 5- (2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (3), and 5-(2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (4). In the present work, the possibility of the preclinical validation of these molecules as anti-inflammatory and analgesic was explored in appropriate in vivo mouse models. Compounds 1, 2 and 4, administered orally as a single dose (30 µmol kg-¹) to the mice showed anti-inflammatory and analgesic properties similar to classic nonsteroidal anti-inflammatory agents. The pharmacological effects were consistent with the inhibitory effect observed on prostaglandin endoperoxide H synthase (PGHS). In fact, both PGHS-1 and PGHS-2 were inhibited by the compounds, with compound 2 being more specific as PGHS-2 inhibitor with a specificity index superior to 70%. Conversely to classical nonsteroidal anti-inflammatory drugs, compound 2 inhibited peroxidase half reaction of the enzyme (IC₅₀ 2.3 µM) while the cyclooxygenase activity of hrPGHS-2 remained unchanged. In vitro experiments were reinforced by docking and molecular dynamics simulations showing arylnitroalkene moiety located in the region of the peroxidase active site, competing with the peroxide intermediate. The absence of toxicity and mutagenicity of the compounds was also demonstrated.

Keywords: Antioxidants, prostaglandin H synthase inhibitors, inflammation, anti-inflammatory therapy, analgesia.